Role of Electrostatic Repulsion in Controlling pH-Dependent Conformational Changes of Viral Fusion Proteins

• Published in: Structure (London) 2013-07, Vol.21 (7), p.1085-1096
• Main Authors: Harrison, Joseph S., Higgins, Chelsea D., O’Meara, Matthew J., Koellhoffer, Jayne F., Kuhlman, Brian A., Lai, Jonathan R.
• Format: Article
• Language: English
• Subjects: Animals; Filoviridae - physiology; Hemagglutinins, Viral - chemistry; Host-Pathogen Interactions; Humans; Hydrogen-Ion Concentration; Influenza A virus - physiology; Models, Molecular; Protein Structure, Secondary; Thermodynamics; Vesiculovirus - physiology; Viral Fusion Proteins - chemistry; Virus Internalization
• ISSN: 0969-2126; 1878-4186
• DOI: 10.1016/j.str.2013.05.009

Viral fusion proteins undergo dramatic conformational transitions during membrane fusion. For viruses that enter through the endosome, these conformational rearrangements are typically pH sensitive. Here, we provide a comprehensive review of the molecular interactions that govern pH-dependent rearrangements and introduce a paradigm for electrostatic residue pairings that regulate progress through the viral fusion coordinate. Analysis of structural data demonstrates a significant role for side-chain protonation in triggering conformational change. To characterize this behavior, we identify two distinct residue pairings, which we define as Histidine-Cation (HisCat) and Anion-Anion (AniAni) interactions. These side-chain pairings destabilize a particular conformation via electrostatic repulsion through side-chain protonation. Furthermore, two energetic control mechanisms, thermodynamic and kinetic, regulate these structural transitions. This review expands on the current literature by identification of these residue clusters, discussion of data demonstrating their function, and speculation of how these residue pairings contribute to the energetic controls. [Display omitted] •Viral fusion proteins undergo pH-dependent conformational changes•Electrostatic repulsion between side chains mediates structural transitions•Histidine-cation (HisCat) and anion-anion (AniAni) interactions are common•Ability of the virus to sense pH changes as it enters the cell plays an important role during the infection Harrison et al. review this problem and point to specific side chain-side chain interactions that regulate envelope glycoprotein conformational changes and allow viral entry.